The human leukocyte and tissue antigenic system HLA like the mouse H-2 system, is thought to be controlled by two closely linked genes; the HLA product is thought to be detected by antisera defining HLA, to induce stimulation of allogeneic lymphocytes and to be responsible for delayed type hypersensitivity responses. We have challenged this concept and believe that three separate products are responsible. A gene S for lymphocyte stimulation and a gene DR for delayed response antigen are believed to be closely linked to but in linkage equilibrium with HLA. Experimentally, we will seek mutations at the DR locus in hybrid mice challenged with parental tumor and will seek to identify the S locus in crosses between H-2 identical mice from different strains. Resolution of cross reactivities between individual HLA specificities is being sought by cytotoxic antiglobulin reactions by neuraminidase treatment of cells used in cytotoxicity testing, by absorption and elution of antibodies from platelets, by cross immunization and by testing broadly reactive sera on different ethnic populations.